An estimated 400,000 anterior cruciate ligament (ACL) injuries occur in the United States each year. The repercussions of ACL injury include instability, pain, damage to the meniscus, and increased risk early onset osteoarthritis (OA). ACL reconstruction is commonly performed in an attempt to restore knee function, but recent studies have questioned its ability to mitigate the development of OA compared to non-operative treatment. In particular, signs of advanced OA are present in more than 50% of ACL reconstruction patients within 10 years of surgery. Thus, regardless of whether the ACL is treated surgically or non-surgically, degenerative changes remain a concern. The precise mechanisms for accelerated joint degeneration after ACL injury are not well understood. This information is crucial to improving the clinical management of ACL injuries. Although many factors likely contribute, altered joint kinematics following ACL injury have been thought to be a crucial factor in the initiation and progression of OA. However, there is a lack of data on in vivo cartilage contact strains during dynamic activities such as walking. Even more importantly, there is limited data characterizing the relationship between altered in vivo cartilage loading and early changes in cartilage morphology and composition in patients with ACL injury. Therefore, the objective of this proposal is to study early mechanical, compositional, and morphologic changes that occur following ACL injury. Our hypothesis is that, in patients with ACL deficiency, regions of elevated cartilage contact strains experience significant compositional changes in cartilage. Moreover, these compositional changes will be followed by changes in focal cartilage thickness in the same regions of increased cartilage loading. To carry out our objective, we will study subjects with acute, isolated, unilateral ACL deficiency and test the same subjects again at one year follow-up. Cartilage contact strains will be evaluated by combining 3D MR-based joint models with high-speed biplanar radiographic images acquired during treadmill gait. Changes in cartilage composition will be measured using T1-rho imaging, a technique sensitive to proteoglycan depletion, which is an early indicator of OA progression. Regions of elevated contact strains will be related to changes in the distribution of cartilage thickness using a combination of MR imaging, 3D modeling techniques, and numerical optimization. These novel data will provide valuable information on the mechanisms contributing to cartilage degeneration after ACL deficiency. Such information is essential to improving the clinical management of patients with ACL injury and potentially provides important insight into the mechanisms contributing to OA.